Intracellular receptors (IR's) are a class of structurally related proteins involved in the regulation of gene expression. The steroid hormone receptors are a subset of this superfamily whose natural ligands are typically comprised of endogenous steroids such as estradiol, progesterone, and cortisol. Man-made ligands to these receptors play an important role in human health and, of these receptors, the glucocorticoid receptor has an essential role in regulating human physiology and immune response. Steroids that interact with the glucocorticoid receptor have been shown to be potent anti-inflammatory agents, although cross-reactivity with other steroid hormone receptors such as the mineralocorticoid, progesterone and androgen receptors can lead to problematic ancillary pharmacology.
The dissociation of transactivation from transrepression at the glucocorticoid receptor is believed to be an approach toward improving the side-effect profile related to steroid therapy. The beneficial anti-inflammatory activity of GR modulators, such as steroids, is believed to occur through the transrepression of genes encoding for proinflammatory cytokines, adhesion molecules and enzymes. Many of the undesirable side-effects associated with such agents are believed to occur through the transactivation, or induction, of gene transcription leading to the downstream perturbation of homeostatic endocrine function. Some of these affected metabolic processes include induced gluconeogenesis, induced amino acid degradation, osteoporosis, suppression of HPA axis, induction of secondary adrenal suppression, changes in electrolyte concentration, changes in lipid metabolism, growth retardation, impaired wound healing and skin thinning. Weak, partial and full agonism of GR related to transrepression and transactivation, including potential antagonism of the receptor regarding transactivation, may be applied to the treatment of inflammatory and autoimmune diseases such as rheumatoid arthritis and asthma. For recent reviews see: (a) Recent Advances in Glucocorticoid Receptor Action; Cato, A. C. B., Schacke, H., Asadullah, K., Eds.; Springer-Verlag: Berlin-Heidelberg, Germany, 2002. (b) Coghlan, M. J.; Elmore, S. W.; Kym, P. R.; Kort, M. E. In Annual Reports in Medicinal Chemistry; Doherty, A. M., Hagmann, W. K., Eds.; Academic Press: San Diego, Calif., USA, 2002; Vol. 37, Ch. 17, pp 167-176.
Glucocorticoid receptor modulators are described in WO 2003/061651, WO2003/086294, WO2004/026248, WO2004/075840 and WO2004093805. An object of the invention is the discovery of novel compounds that modulate the glucocorticoid receptor. Another object of the invention is the discovery of novel glucocorticoid receptor modulators with superior transactivation and transrepression activity profiles. It is believed that such compounds would have potent anti-inflammatory and immunosuppressive activity and possess advantages over current steroid therapies with respect to side effects, efficacy, toxicity and/or metabolism.